Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma (NHL) that remains largely incurable due to development of drug resistance. Disease progression in MCL is invariably associated with unrestrained proliferation of tumor cells caused by dysregulated CDK4 activity and aberrant cyclin D1 expression. Targeting CDK4, therefore, is a rational approach to MCL therapy. The first phase I clinical trial targeting CDK4 with PD 0332991 (palbociclib, the first selective CDK4/6 inhibitor) in recurrent MCL resulted in durable clinical responses with tumor regression in some MCL patients. Inhibition of CDK4, therefore, not only prevents proliferation of cancer cells but also enhances their vulnerability. Ongoing clinical trials combining palbociclib with bortezomib or with ibrutinib, which inhibits BTK required for MCL survival, support the clinical efficacy of targeting CDK4. Longitudinal integrative analysis of whole transcriptome?sequencing and whole exom- sequencing further reveals that inhibition of CDK4 leads to prolonged early G1 arrest (pG1) in all patients but clinical response is associated with differential regulation of genes that are involved in PI3K inactivation, metabolism and redox stress. To address the underlying mechanism, we discovered that pG1 induced repressive chromatin remodeling by differential regulation of EZH1 and EZH2, histone methyltransferases for H3K27me2/3, in responding patients, and timely inhibition of EZH1/EZH2 led to synergistic killing of MCL cells in pG1. These results suggest that chromatin remodeling is a critical proximal event in pG1 reprogramming. Moreover, pG1 sensitizes MCL cells to killing by ibrutinib and by inhibition of PI3K, and this requires the action of the FOXO1 transcription factor, which is activated and localized to the nucleus in pG1. FOXO1 is a central component of the PI3K signaling and also acts as a tumor suppressor in a context-dependent manner. Based on our novel preliminary findings, we hypothesize that induction of pG1 by CDK4 inhibition causes specific epigenetic alterations that modify FOXO1's access to its target genes, which in turn alters the expression of FOXO1-dependent cytotoxic genes for clinical response to targeting CDK4 in MCL. Our goal is to advance hypothesis-driven, effective and durable cell cycle therapy in cancer by defining the mechanisms of cell cycle reprogramming. To achieve this goal, we will test our hypothesis in two Specific Aims: 1) To elucidate the role of EZH1 and EZH2 in chromatin remodeling in pG1 reprogramming by elucidate chromatin remodeling in pG1 transcriptional reprogramming and determining the functional consequence of cell cycle regulation of EZH1/EZH2; and 2) To define the role of FOXO1 in CDK4 inhibitor sensitization to BTK or PI3K inhibition by determine the significance of cell cycle regulation of FOXO1 and identifying the transcriptional targets of FOXO1 that mediates pG1 sensitization to clinical response. Successful completion of the proposed studies should shed light on the mechanism of cell cycle control of chromatin remodeling and FOXO activation, which has important and broad clinical implications.